Compositions and methods for treating motor disorders

ABSTRACT

This invention provides methods utilizing ketamine for the treatment of motor disorders and/or side effects associated with certain medications used in the treatment of motor disorders. For example, in some embodiments, methods are provided for treating side effects associated with the administration of levodopa to a subject having Parkinson&#39;s disease, by administering a dose of ketamine or a pharmaceutically acceptable salt thereof. In particular, the invention provides methods for reducing dyskinesia associated with motor disorder (e.g., Parkinson&#39;s disease) treatments, and effective doses of ketamine or a pharmaceutically acceptable salt

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/574,346, filed Nov. 15, 2017, allowed as U.S. Pat. No.11,426,366, which is a Section 371 U.S. national stage entry ofInternational Patent Application No. PCT/US2016/032155, InternationalFiling Date May 12, 2016, which claims the benefit of expired U.S.Provisional Patent Application No. 62/162,403, filed May 15, 2015, thecontents of which are incorporated by reference in their entireties.

FIELD OF THE INVENTION

This invention provides methods utilizing ketamine for the treatment ofmotor disorders and/or side effects associated with certain medicationsused in the treatment of motor disorders. For example, in someembodiments, methods are provided for treating side effects associatedwith the administration of levodopa (L-DOPA) to a subject havingParkinson's disease, by administering a dose of ketamine or apharmaceutically acceptable salt thereof. In particular, the inventionprovides methods for reducing dyskinesia associated with motor disorder(e.g., Parkinson's disease) treatments, and effective doses of ketamineor a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is the 2^(nd) most common progressiveneurodegenerative disease with the cardinal motor symptoms of tremor,rigidity, postural instability and bradykinesia (Olanow et al., 2009).These motor symptoms correspond to the loss of dopaminergic neurons withcell bodies located in the substantia nigra and axonal projections tothe striatum leading to reduced dopamine (DA) levels. The most commontreatment for PD consists of DA replacement therapy utilizing either theDA precursor L-DOPA or DA receptor agonists. These therapies becomeunsatisfactory as the disease progresses due to a variety of short-termand long-term side effects that occur with dose escalation, includingthe most common and debilitating side effect L-DOPA-induced dyskinesias(LID). Therefore, there is an urgent need to develop non-dopaminergictherapies. An effective treatment of LID to extend the useful lifetimeof L-DOPA treatment is a critical unmet need in PD therapy.

SUMMARY

Low-dose sub-anesthetic ketamine infusion treatment has led to along-term reduction of treatment-resistant depression and posttraumaticstress disorder (PTSD) symptom severity, as well as reduction of chronicpain states, including migraine headaches. Ketamine also is known tochange oscillatory electric brain activity. One commonality betweenmigraine headaches, depression, PTSD, Parkinson's disease (PD) andL-DOPA-induced dyskinesia (LID) is hypersynchrony of electric activityin the brain, including the basal ganglia. Therefore, experimentsconducted during the course of developing embodiments for the presentinvention investigated the use of low-dose ketamine in the treatment ofPD and LID. A long-term therapeutic effect of low-dose ketamine infusion(0.15-0.3 mg/kg/hr for 72 hrs) from five PD patient case studies(reduced dyskinesia, improved on time, and reduced depression) wasshown. Additionally, ketamine (5-20 mg/kg) led to long-termdose-dependent reduction of abnormal involuntary movements in apreclinical rodent model of LID, but only when low-dose ketamine wasgiven for 10 hours and not with a single acute low-dose ketamineinjection.

Accordingly, this invention provides methods utilizing ketamine for thetreatment of motor disorders and/or side effects associated with certainmedications used in the treatment of motor disorders. For example, insome embodiments, methods are provided for treating side effectsassociated with the administration of levodopa to a subject havingParkinson's disease, by administering a dose of ketamine or apharmaceutically acceptable salt thereof. In particular, the inventionprovides methods for reducing dyskinesia associated with motor disorder(e.g., Parkinson's disease) treatments, and effective doses of ketamineor a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides methods ofpreventing, attenuating, and/or treating a patient suffering from amotor disorder, comprising administering to the patient a compositioncomprising a dose of ketamine or a pharmaceutically acceptable saltthereof to ameliorate the symptoms of the motor disorder. In someembodiments, the methods further comprise administration of carbidopa.

In some embodiments, the ketamine is administered at a dose from about0.15 mg/kg/hour to about 10 mg/kg/hour for at least two hours (e.g., 2,3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 72, 100, etc). In someembodiments, the ketamine is administered at a dose from about 0.15mg/kg/hour to about 5 mg/kg/hour for at least two hours (e.g., 2, 3, 5,10, 15, 20, 25, 30, 40, 50, 60, 70, 72, 100, etc). In some embodiments,the ketamine is administered at a dose from about 0.15 mg/kg/hour toabout 2 mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20,25, 30, 40, 50, 60, 70, 72, 100, etc). In some embodiments, the ketamineis administered at a dose from about 0.15 mg/kg/hour to about .5mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20, 25, 30,40, 50, 60, 70, 72, 100, etc). In some embodiments, the ketamine isadministered at a dose from about 0.15 mg/kg/hour to about 0.3mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20, 25, 30,40, 50, 60, 70, 72, 100, etc).

In some embodiments, the ketamine is administered in a delayed releaseformulation. In some embodiments, the patient is human.

In some embodiments, administration of the composition comprising a doseof ketamine results in the patient experiencing chemical-induced deepbrain stimulation. In some embodiments, such chemical-induced deep brainstimulation results in prevention, attenuation and/or treating of thesymptoms of the motor disorder.

In some embodiments, the motor disorder is dyskinesia. In someembodiments, the motor disorder is tardive dyskinesia.

In some embodiments, the motor disorder is selected from the groupconsisting of Parkinson's disease, dopamine-responsive dystonia,multiple sclerosis, Huntington's disease, Creutzfeld-Jakob disease,amyotrophic lateral sclerosis, and Alzheimer's disease.

In some embodiments, the motor disorder is a side effect associated withadministration of a medication to the patient. In some embodiments, themedication is a medication known to be useful for treating aneurodegenerative disorder. For example, in some embodiments, theneurodegenerative disorder is selected from the group consisting ofParkinson's disease, dopamine-responsive dystonia, multiple sclerosis,Huntington's disease, Creutzfeld-Jakob disease, amyotrophic lateralsclerosis, and Alzheimer's disease. In some embodiments, the medicationis a medication known to be useful for treating a psychotic disorder.For example, in some embodiments, the psychotic disorder is selectedfrom the group consisting of schizophrenia, schizophreniform disorder,bipolar disorder, and schizoaffective disorder.

In some embodiments, the medication is selected from the groupconsisting of levodopa, haloperidol, fluphenazine, flunarizine,metoclopramide, prochlorperazine, chlorpromazine, triflupromazine,thiordazine, mesoridazine, trifluoperazine, perphenazine, perazine,chlorprothixene, droperidol, pimozide, loxapine, clozapine, quetiapine,olanzapine, risperidone, ziprasidone, lloperidone, tiapride, sulpride,clebopride, remoxipride, veralipride, amisulpride, molindone,aripiprazole, amoxapine, flunarizine, cinnarizine, bromocriptine,pergolide, cabergoline, apomorphine, lisuride, ropinirole, pramipexole,and melatonin.

In some embodiments wherein the medication is levodopa, the ketamineadministration does not reduce efficacy of the levodopa administration.

In some embodiments, the ketamine within the composition is a metaboliteof ketamine. For example, in some embodiments, one or more of thefollowing metabolites of ketamine is administered with or in lieuketamine: R-norketamine (NK), R-dehydronorketamine (DHK), S-norketamine(NK), S-dehydronorketamine (DHK), (2R,6R)-hydroxynorketamine (HNK), and(2S,6S)-hydroxynorketamine (HNK). In certain embodiments, the presentinvention provides methods of treating a human suffering fromParkinson's disease, the method comprising administering to the human acomposition comprising a dose of levodopa and a composition comprising adose of ketamine or a pharmaceutically acceptable salt thereof. In someembodiments, the methods further comprise administration of carbidopa.

In some embodiments, the ketamine is administered at a dose from about0.15 mg/kg/hour to about 10 mg/kg/hour for at least two hours (e.g., 2,3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 72, 100, etc). In someembodiments, the ketamine is administered at a dose from about 0.15mg/kg/hour to about 5 mg/kg/hour for at least two hours (e.g., 2, 3, 5,10, 15, 20, 25, 30, 40, 50, 60, 70, 72, 100, etc). In some embodiments,the ketamine is administered at a dose from about 0.15 mg/kg/hour toabout 2 mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20,25, 30, 40, 50, 60, 70, 72, 100, etc). In some embodiments, the ketamineis administered at a dose from about 0.15 mg/kg/hour to about .5mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20, 25, 30,40, 50, 60, 70, 72, 100, etc). In some embodiments, the ketamine isadministered at a dose from about 0.15 mg/kg/hour to about 0.3mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20, 25, 30,40, 50, 60, 70, 72, 100, etc).

In some embodiments, the ketamine is administered in a delayed releaseformulation. In some embodiments, the patient is human. In someembodiments, the ketamine and the levodopa are concurrently active inthe human.

In some embodiments, the ketamine is administered to the human beforethe human develops dyskinesia associated with the levodopaadministration. In some embodiments, the ketamine is administered to thehuman after the human develops dyskinesia associated with the levodopaadministration. In some embodiments, the ketamine is administered to thehuman before the administration of the levodopa.

In some embodiments, the ketamine within the composition is a metaboliteof ketamine. For example, in some embodiments, one or more of thefollowing metabolites of ketamine is administered with or in lieuketamine: R-norketamine (NK), R-dehydronorketamine (DHK), S-norketamine(NK), S-dehydronorketamine (DHK), (2R,6R)-hydroxynorketamine (HNK), and(2S,6S)-hydroxynorketamine (HNK).

In certain embodiments, the present invention provides kits comprisingtherapeutically effective dosages of ketamine (and/or metabolites ofketamine) and levodopa, and further comprising instructions foradministering the ketamine and the levodopa to a subject suffering fromdyskinesia.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-D. UPDRS Dyskinesia score and % dyskinesia on time is reduced bylow-dose ketamine infusion in case #1. The charts in (A-C) show the %time the patient spent in on, off, or dyskinetic on time, or was asleepduring 24 hrs, based on the patient diary. In (A) the average of 4 pre-Kdays is shown and in (B) the average of the 1st week post-K. In (C) theaverage of weeks 2-4 post-K is depicted, and during this time the LIDhad completely resolved. K=72 hr low-dose ketamine-infusion. The graph(D) shows the UPDRS dyskinesia score (sum of items 32-34) before, duringand after the low-dose ketamine infusion (see, Sherman S J, et al., Case

Reports in Neurology 2016; 8:53-58).

FIG. 2A-B. Verification of unilateral 6-OHDA lesion. (A) Electrochemicaldetection of striatal DA content. The DA content (mean±SEM) is reducedby >95% in the lesioned side, and [DA] was unchanged by an acute i.p.injection of 20 mg/kg ketamine (n=7) vs. saline (n=5) 30 min before ratswere euthanized, showing that there is no acute effect on overallstriatal DA levels by ketamine in these animal with multiple priorexposures to ketamine (2way ANOVA, Bonferroni post-hoc test). (B)Semi-quantitative western analysis of striatal tyrosine hydroxylase (TH)expression. TH was normalized to (3-actin as internal standard, meanvalues±SEM are plotted, and expression is reduced by 87% in the lesionedside (n=15; two-tailed t test) verifying the severity of the lesion. TheInset shows example blots (UL=unlesioned, L=lesioned). Statisticalsignificant differences are depicted by asterisks (***p<0.001;ns=non-significant) (see, Bartlett M J, et al., Neuroscience Letters2016; 612:121-125).

FIG. 3A-D. Long-term dose-dependent reduction of LID after thelow-dose-ketamine ‘infusion’ paradigm in the preclinical model. (A)Schematic of the 10 hour experimental protocol to mimic a ketamineinfusion. (B) Severely dyskinetic LID rats (cohort #1) were tested withL-DOPA (7 mg/kg) every 3-4 days (white bars). The blue bars depict thedays of ketamine challenges (K). The graph depicts mean limb, axial andorolingual (LAO)-AIMs±SEM; n=5; repeated measures ANOVAs vs. precedingbaseline testing sessions; Tukey post-hoc tests; *p<0.05; **p<0.01;***p<0.005). When comparing the pre-K (20 mg/kg) and the last testingsession (blue line), a significantly reduced LAO-AIMs score remained,indicating a new stable lower level of LAO AIMs (*p<0.05; two tailed ttest). (C) Ketamine ‘infusion’ did not have a significant effect onL-DOPA-induced contralateral locomotor scores in these animals and didnot induce ipsilateral rotations in the presence of L-DOPA. (D) Acutelow-dose-ketamine does not reduce LID. A separate cohort #2 ofmoderately dyskinetic LID rats was challenged with L-DOPA (5 mg/kg)every 3-4 days and AIMs were evaluated. The blue bars depict the days ofacute ketamine (K; i.p.) challenges (mean LAO-AIMs±SEM; n=9; repeatedmeasures ANOVAs vs. preceding baseline testing sessions; ns) (see,Bartlett M J, et al., Neuroscience Letters 2016; 612:121-125).

FIG. 4A-C. Low-dose sub-anesthetic racemic ketamine infusion once a weekreduces the development of LID in the preclinical model. Unilaterally6-hydroxydopamine (6-OHDA)-lesioned PD rats were injected daily withL-DOPA (days 0-13: 6 mg/kg; days 14-28: 12 mg/kg; i.p.) to inducedyskinesia and tested for limb, axial and oral (LAO) abnormalinvoluntary movements (AIMs) twice a week for 3 hours by blindedinvestigators. In panel (A) the mean LAO AIMs scores±SEM are plottedshowing a 50% reduction after racemic low-dose ketamine infusions. Theblack arrows point to the days of the 10-hours racemic ketamine,R-ketamine or vehicle infusion paradigm (n=9 per group, *p<0.05, ANOVAs,Tukey post hoc tests). The scatter plots depicting every animalseparately in both the 6 mg/kg L-DOPA period in (B) and the 12 mg/kgL-DOPA period in (C) reveal that there are responders and non-respondersin the racemic ketamine-treated group: 4 of 9 animals did not developany dyskinesia or only very subtle dyskinesia, while only 1 in theR-ketamine-treated group, and none in the vehicle control group. Theblack lines depict the mean value per groups.

FIG. 5A-D. Effects of racemic ketamine injection (20 mg/kg) onhigh-frequency (HFO) and beta band oscillations in the motor cortex (M1)and dorsolateral striatum (DLS). Using the 10-hour racemic ketamineparadigm (5 i.p. injections every 2 hours), we measured simultaneouslocal-fieldactivity in multiple brain structures in two awake andbehaving naïve rats. Recordings were acquired from a 64 channel fixedelectrode array. Average response across 2 animals and 5 sessions. (A+B)Power spectrogram from a 10 hour session created by averaging spectraacquired from 5 recording sessions. Vertical lines indicate K injectiontimes. A clear increase in high-frequency activity (120-140 Hz) wasobserved after each ketamine injection in both motor cortex (M1) anddorsolateral striatum (DLS). (C) Plot of mean coherence in allfrequencies <200 Hz. Coherence in the HFO frequency band increasedfollowing each injection. (D) Plot of the mean coherence in the HFO andbeta bands (n=5 sessions). Thin lines indicate SEM. Coherence in thesetwo bands was anti-correlated (r=−0.65). Coherence in the HFO bandappeared to increase with successive injections while coherence in thebeta band decreased.

FIG. 6A-C. Effects of racemic ketamine injection (20 mg/kg) onhigh-frequency (HFO), gamma and beta band oscillations in the motorcortex (M1) and dorsolateral striatum (DLS) of a rodent Parkinson'sdisease model. Using the 10-hour racemic ketamine paradigm (5 i.p.injections every 2 hours), we measured simultaneous local-field activityin multiple brain structures in three awake and behaving unilateral6-hydroxydopamine (6-OHDA)-lesioned rats, a common model of Parkinson'sdisease. Recordings were acquired from a 64 channel fixed electrodearray. Average response across 3 animals. Power spectrogram from a 10hour session created by averaging spectra acquired. Vertical linesindicate ketamine injection times. A clear increase in high-frequencyactivity (120-140 Hz) and gamma band activity (40-60 Hz) was observedafter each ketamine injection in both DLS (A) and M1 (B). Beta-Gammacross-frequency coupling (CFC) in the DLS of 6-OHDA-lesioned PD animalsis reduced following each ketamine injection (C). Units are in z-scoresrelative to baseline CFC during the 20 minutes prior to the firstinjection. Cross-frequency coupling measures the degree to whichfluctuations in the power of the high-frequency oscillation (gamma) iscorrelated with the phase of the lower-frequency oscillation (beta).Error bars indicate SEM (n=15 sessions across 3 animals).

DETAILED DESCRIPTION OF THE INVENTION

Parkinson's disease (PD) is the 2^(nd) most common progressiveneurodegenerative disease with the cardinal motor symptoms of tremor,rigidity, postural instability and bradykinesia (Olanow et al., 2009).These motor symptoms correspond to the loss of dopaminergic neurons withcell bodies located in the substantia nigra and axonal projections tothe striatum leading to reduced dopamine (DA) levels. The most commontreatment for PD consists of DA replacement therapy utilizing either theDA precursor L-DOPA or DA receptor agonists. These therapies becomeunsatisfactory as the disease progresses due to a variety of short-termand long-term side effects that occur with dose escalation, includingthe most common and debilitating side effect L-DOPA-induced dyskinesias(LID). Therefore, there is an urgent need to develop non-dopaminergictherapies. An effective treatment of LID to extend the useful lifetimeof L-DOPA treatment is a critical unmet need in PD therapy.

Low-dose ketamine is used to treat various chronic pain syndromes,especially those that have a neuropathic component, and studies on theeffect of prolonged infusion (4-14 days) show long-term analgesiceffects up to 3 months following infusion (Niesters et al., 2014).Recent publications also showed that low-dose ketamine infusionparadigms are safe and well tolerated in clinical trials fortreatment-resistant depression (Diamond et al., 2014; Lapidus et al.,2014; Murrough, Iosifescu, et al., 2013; Murrough, Perez, et al., 2013)and PTSD (Feder et al., 2014). Low-dose ketamine has led to a reductionof treatment-resistant depression; it also reduced PTSD symptom severityand comorbid depression. The pathophysiology of LID and motorfluctuations is uncertain, although hypotheses include an imbalancebetween the direct and indirect striatofugal pathways within the basalganglia (BG), due to repeated daily administration of L-DOPA, theproduction of “denervation super sensitivity” of DA receptors, and as aresult also hypersynchrony of electric activity and maladaptive plasticchanges in the brain, including in the BG, which is a commonalitybetween LID, depression and PTSD. Based on this information it washypothesized that use of low-dose ketamine infusions might help withtreatment of PD, especially LID. Therefore, low-dose-ketamine infusionswere investigated in five PD patient case studies and the standardpreclinical LID model.

Experiments conducted during the course of developing embodiments forthe present invention investigated the use of low-dose ketamine in thetreatment of PD and LID. A long-term therapeutic effect of low-doseketamine infusion (0.15-0.3 mg/kg/hr for 72 hrs) from five PD patientcase studies (reduced dyskinesia, improved on time, and reduceddepression) was shown. Additionally, in a preclinical rodent model ofLID, ketamine (5-20 mg/kg) led to long-term dose-dependent reduction ofabnormal involuntary movements, only when low-dose ketamine was givenfor 10 hours and not with a single acute low-dose ketamine injection.The utility of ketamine for preoperative management with Parkinson'sDisease patients has been described (see, e.g., Wright, et al., 2009),wherein an acute effect of ketamine on levodopa-induced dyskinesia (LID)is detected. The technology described herein, however, is not derivativeof this unsurprising and expected observation. Indeed, an acute effectof ketamine and other NMDA-blocking drugs on LID is well-known. Forexample, the NMDA blocking drug, amantadine is in routine clinical useto acutely treat LID. The acute effect of ketamine, described by Wrightet al., is only useful in the proscribed setting of anesthesia care. Incontrast, the technology described herein pertains to the use of aparticular and unique treatment protocol that induces long-lasting orpermanent beneficial effects to reduce or eliminate LID. Such technologydescribes a separate line of reasoning built on separate experimentalobservations and clinical practice. Unlike the use of ketamine for acuteeffects, the treatment regimen described herein involves continuousinfusion of low-dose ketamine which cannot be attributed to the merepresence of an NMDA-blocking drug producing a simple pharmacologicaleffect. Blockade of NMDA receptors alone as theorized by Wright et al.does not lead to an extended beneficial effect. Instead, as shown by theexperiments described herein, long-lasting effects are dependent onadditional properties of ketamine acting though other neurologicalmechanisms such as the induction of specific changes in the oscillatoryactivity of brain regions affected by Parkinson disease.

Additionally, the experimental findings described herein show thatlow-dose-ketamine infusion also has a preventative effect by reducingthe severity of LID when used during the period of developing LID.

Accordingly, this invention encompasses preventing, attenuating, and/ortreating a motor disorder and/or side effects related to the treatmentof a motor disorder.

For example, this invention encompasses use of ketamine and derivativesthereof (e.g., metabolites of ketamine) for preventing, attenuating,and/or treating a motor disorder including, but not limited to,Parkinson's disease, dopamine-responsive dystonia, multiple sclerosis,Huntington's disease, Creutzfeld-Jakob disease, amyotrophic lateralsclerosis, and Alzheimer's disease.

For example, this invention encompasses use of ketamine and derivativesthereof for preventing, attenuating, and/or treating side effectsrelated to the treatment of a motor disorder (e.g., side effects ormovement disorders that are associated with dopamine-related drugs)(e.g., L-DOPA-induced dyskinesia (LID)). In some embodiments, the use ofketamine and/or derivatives thereof (e.g., metabolites of ketamine)permits the simultaneous use of a higher than normal dosage of L-DOPA orother dopamine-related drug while preventing, attenuating, and/ortreating side effects related to the treatment of a motor disorder(e.g., side effects or movement disorders that are associated withdopamine-related drugs) (e.g., L-DOPA-induced dyskinesia (LID)).

For example, this invention encompasses use of ketamine and derivativesthereof (e.g., metabolites of ketamine) for preventing, attenuating,and/or treating side effects related to the treatment of a psychoticdisorder (e.g., tardive dyskinesia related to use of neurolepticmedication based treatment of, for example, schizophrenia,schizophreniform disorder, bipolar disorder, and schizoaffectivedisorder) (e.g., treatment with a neuroleptic medication such ashaloperidol).

For example, this invention encompasses use of ketamine and derivativesthereof (e.g., metabolites of ketamine) for preventing, attenuating,and/or treating side effects related to the use of medications such as,for example, levodopa, haloperidol, fluphenazine, flunarizine,metoclopramide, prochlorperazine, chlorpromazine, triflupromazine,thiordazine, mesoridazine, trifluoperazine, perphenazine, perazine,chlorprothixene, droperidol, pimozide, loxapine, clozapine, quetiapine,olanzapine, risperidone, ziprasidone, lloperidone, tiapride, sulpride,clebopride, remoxipride, veralipride, amisulpride, molindone,aripiprazole, amoxapine, flunarizine, cinnarizine, bromocriptine,pergolide, cabergoline, apomorphine, lisuride, ropinirole, pramipexole,and melatonin.

For example, this invention encompasses use of ketamine and derivativesthereof (e.g., metabolites of ketamine) for preventing, attenuating,and/or treating motor disorder side effects in a patient with PD,including but not limited to dyskinesia or other motor disorder sideeffects or movement disorders that are associated with dopamine-relateddrugs.

Such methods of the invention comprises, for example, administering to apatient in need thereof a therapeutic dose of ketamine and/or aderivative thereof (e.g., a pharmaceutically acceptable salt).

Optionally in combination with a therapeutic dose of ketamine and/or aderivative thereof (e.g., metabolites of ketamine), the inventionencompasses administering to the patient in need thereof a compound thattargets the same, a similar, or a different drug pathway, one that isuseful in treating L-DOPA-induced dyskinesia (LID) or other movementdisorders or motor disorder side effects associated withdopamine-related drugs, one that is useful in treating PD, or one thatis useful for treating both LID or other movement disorders, or motordisorder side effects associated with dopamine-related drugs and PD.This additional compound may also be useful such that the effective doseof L-DOPA or other dopamine-related drug that is necessary to treat PDis reduced. In some embodiments, the invention contemplatesadministering to the patient in need thereof L-DOPA, in addition to acompound that targets the same, a similar, or a different drug pathway,one that is useful in treating L-DOPA-induced dyskinesia (LID), one thatis useful in treating PD, or one that is useful for treating both LID orother movement disorders or motor disorder side effects associated withdopamine-related drugs and PD. The dopamine-related drugs encompassed bythe invention include drugs that increase the activity of the dopaminereceptor, including dopamine agonists and partial agonists, whetheracting directly or indirectly, as well as dopamine precursors, such asL-DOPA. In a preferred embodiment, the dopamine-related drug treatmentis L-DOPA therapy.

In some embodiments, the dopamine-related drug may be a dopaminereceptor agonist, including, but not limited to bromocriptine,pergolide, cabergoline, apomorphine, and lisuride, or a non-ergolinedopamine agonist, including, but not limited to ropinirole orpramipexole.

In yet other embodiments, the methods of the invention encompasspreventing, attenuating, and/or treating any of the motor disorder sideeffects described herein, associated with a combination ofdopamine-related drug treatments, such as a combination of a dopamineprecursors, a combination of dopamine agonists or partial agonists, anda combination of one or more dopamine precursors and one or moredopamine agonists or partial agonists.

Dopamine precursors such as L-DOPA are often administered with a DOPAdecarboxylase inhibitor (DDCI) (also known as aromatic L-amino aciddecarboxylase inhibitors (AAADI)). Non-limiting examples of suchcompounds contemplated by the invention include benserazide (Madopar,Prolopa, Modopar, Madopark, Neodopasol, and EC-Doparyl); carbidopa(Lodosyn, Sinemet, Parcopa, and Atamet); and Methyldopa (Aldomet,Aldoril, Dopamet, and Dopegyt).

In addition to DDCIs, L-DOPA or other dopamine precursors are also oftenadministered with compounds that inhibit the action of catechol-O-methyltransferase (COMT inhibitors). Non-limiting examples of COMT inhibitorscontemplated by the invention are entacapone, tolcapone, and nitecapone.

The methods of the invention, therefore, encompass preventing,attenuating, and/or treating any of the motor disorder side effectsdescribed herein, associated with L-DOPA treatment or treatment withanother dopamine-related drug, L-DOPA treatment or otherdopamine-related drug treatment in combination with DDCI (AAADI)treatment, L-DOPA treatment or other dopamine-related drug treatment incombination with COMT inhibitors, and L-DOPA treatment or otherdopamine-related drug treatment in combination with DDCI (AAADAI)treatment and COMT inhibitors.

In one embodiment, the methods of the invention encompass preventing,attenuating, and/or treating any of the motor disorder side effectsdescribed herein, associated with administering the combination ofcarbidopa and levodopa. In one embodiment, the combination of carbidopaand levodopa is administered as Rytary.

In one embodiment, the methods of the invention encompass preventing,attenuating, and/or treating any of the motor disorder side effectsdescribed herein, associated with administering the combination ofcarbidopa, levodopa, and entacapone. In one embodiment, the combinationof carbidopa, levodopa, and entacapone is administered as Stalevo.

In another embodiment, the methods of the invention encompasspreventing, attenuating, and/or treating PD itself, including themovement disorders associated with PD.

In one embodiment, this invention provides a method of prevention,attenuation, and/or treatment of motor disorder side effects, includingbut not limited to dyskinesia, that are associated with L-DOPA therapyor other dopamine-related drugs in Parkinson's patients comprisingadministering to a patient in need thereof a therapeutic dose ofketamine.

In one preferred embodiment, the invention provides a method ofpreventing, attenuating, and/or treating Parkinson's disease, comprisingadministering to a patient in need thereof a dopamine-related drug andmost preferably, L-DOPA, in combination with a therapeutic dose ofketamine or a pharmaceutically acceptable acid addition salt thereof.

In some embodiments, the invention provides methods for treating one ormore symptoms of Parkinson's disease. Examples of such symptoms includebut are not limited to dyskinesia, hyperkinesia, speech changes, loss offacial expression, cognitive dysfunction, mood swings, emotionallability, euphoria, bipolar syndrome, anxiety, aphasia, dysphasia, ordisturbances, dementia or confusion, depression, fear, anxiety, memorydifficulties, slowed thinking, sexual dysfunction, fatigue, aching, andloss of energy.

For all the conditions described herein, one of ordinary skill in theart will appreciate how to determine the presence or absence ofcharacteristic symptoms and also how to diagnose these conditions. Anumber of criteria for diagnosing disease are useful for characterizingthese conditions such as for example, NINCDS-ADRDA criteria, the ICD-IOcriteria, and/or the DSM-IV criteria. Other manuals useful in diagnosingthe conditions described herein include for example, but are not limitedto Oppenheimer's Diagnostic Neuropathology: A Practice Manual;Harrison's Principles of Internal Medicine (Ed. Kasper et al, 16th Ed.2005 McGraw Hill, Columbus, Ohio); Goetz: Textbook of Clinical Neurology(Eds. Goetz, Pappert, 2nd Ed. 2003, W. B. Saunders, Philadelphia, Pa.).One of ordinary skill will be aware of other such manuals routinely usedin the art to diagnose these conditions.

Ketamine

((RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone) is particularlypreferred for use with this invention, including pharmaceuticallyacceptable salts thereof. This invention also includes the use ofprodrugs of the compounds of the formulas provided, specificallyderivatives of the compounds of the formulas that are inactive but areconverted to an active form in the body following administration.

In one embodiment, ketamine and/or a related compound(s) is administeredin combination with one or more additional compound(s). The additionalcompound(s) may have actions that are similar to, synergistic to, ordifferent than ketamine and/or its related compound(s).

In one embodiment, ketamine and/or a related compound(s) is administeredoptionally in combination with one or more additional compound(s) listedabove for prevention, attenuation, and/or treatment of dyskinesia orother motor disorder side effect that is associated with L-DOPA therapyor other dopamine-related drugs in Parkinson's patients. In anotherembodiment, ketamine and/or a related compound(s) is administeredoptionally in combination with one or more additional compound(s) listedabove for prevention, attenuation, and/or treatment of PD.

In yet another embodiment, L-DOPA is administered to a PD patient inneed thereof, and following this administration, by the methodsdescribed herein, ketamine and/or a related compound(s) is administeredoptionally in combination with one or more additional compound(s) listedabove for prevention, attenuation, and/or treatment of dyskinesia thatis associated with L-DOPA therapy. In yet another embodiment, L-DOPA isadministered to a PD patient in need thereof following theadministration of ketamine and/or a related compound(s) optionally incombination with one or more additional compound(s) listed above forprevention, attenuation, and/or treatment of dyskinesia that isassociated with L-DOPA therapy.

In yet another embodiment, L-DOPA is administered to a PD patient inneed thereof, and following this administration, by the methodsdescribed herein, ketamine and/or a related compound(s) is administeredafter the development of motor side effects, optionally in combinationwith one or more additional compound(s) listed above for prevention,attenuation, and/or treatment of dyskinesia that is associated withL-DOPA therapy.

In yet another embodiment, L-DOPA is administered to a PD patient inneed thereof, and following this administration, by the methodsdescribed herein, ketamine and/or a related compound(s) is administeredprior to the development of motor side effects, optionally incombination with one or more additional compound(s) listed above forprevention, attenuation, and/or treatment of dyskinesia that isassociated with L-DOPA therapy.

In one embodiment, ketamine and/or a related compound(s) is administeredin combination with at least one NMDA receptor antagonist. In anotherembodiment, ketamine and/or a related compound(s) is administered incombination with remacemide. In yet another embodiment, ketamine and/ora related compound(s) is administered in combination with amantadine.

The doses of the compounds used in treating the disorders describedherein in accordance with this invention will vary in the usual way withthe seriousness of the disorder, the weight, and metabolic health of theindividual in need of treatment. The preferred initial doses for thegeneral patient population will be determined by routine dose-rangingstudies, as are conducted, for example, during clinical trials.Therapeutically effective doses for individual patients may bedetermined, by titrating the amount of drug given to the individual toarrive at the desired therapeutic or prophylactic effect, whileminimizing side effects.

Useful doses of ketamine are from about 0.25 to about 500 mg/day, fromabout 0.25 to about 450 mg/day, from about 0.25 to about 300 mg/day,from about 0.25 to about 290 mg/day, from about 0.25 to about 280mg/day, from about 0.25 to about 265 mg/day, from about 0.25 to about262 mg/day, from about 0.25 to about 255 mg/day, from about 0.25 toabout 250 mg/day, from about 0.25 to about 245 mg/day, from about 0.25to about 240 mg/day, from about 0.25 to about 225 mg/day, from about0.25 to about 220 mg/day, from about 0.25 to about 200 mg/day, fromabout 0.25 to about 180 mg/day, from about 0.25 to about 175 mg/day,from about 0.25 to about 150 mg/day, from about 0.25 to about 149mg/day, from about 0.25 to about 140 mg/day, from about 0.25 to about125 mg/day, from about 0.25 to about 115 mg/day, from about 0.25 toabout 110 mg/day, from about 0.25 to about 105 mg/day, from about 0.25to about 100 mg/day, from about 0.25 to about 95 mg/day, from about 0.25to about 90 mg/day, from about 0.25 to about 76 mg/day, from about 0.25to about 70 mg/day, from about 0.25 to about 60 mg/day, from about 0.25to about 55 mg/day, from about 0.25 to about 50 mg/day, from about 0.25to about 48 mg/day, from about 0.25 to about 40 mg/day, from about 0.25to about 30 mg/day, from about 0.25 to about 25 mg/day, from about 0.25to about 20 mg/day, from about 0.25 to about 10 mg/day, from about 2.5to about 10 mg/day, from about 2.5 to about 7.5 mg/day. In someembdiments, the dose of ketamine and/or related compounds is from about2.5 to about 150 mg/day. In some embodiments, the dose of ketamineand/or related compounds is from about 2.5 to about 100 mg/day. In someembodiments, the daily dose of ketamine and/or related compounds isabout 1 mg, 2 mg, 2.5 mg, 5 mg, 7 mg, 7.5 mg, 9 mg, 10 mg, 12 mg, 15 mg,17 mg, 19 mg, 20 mg, 25 mg, 50 mg, 55 mg, 60 mg, 75 mg, 85 mg, 100 mg,110 mg, 125 mg, 150 mg, 180 mg, 200 mg, 225 mg, 250 mg, 280 mg, 290 mg,300 mg, 310 mg, 325 mg, 350 mg, 375 mg, 380 mg, 390 mg, 399 mg, 400 mg,415 mg, 425 mg, 450 mg, 475 mg, 480 mg, 490 mg, 500 mg. Administrationschedules may also be altered to achieve a therapeutically effectiveconcentration of compound to treat the disorder or symptoms describedherein. Ketamine administration schedules and dosages may also varydepending on the type of delivery (e.g., intranasal, transdermal, oral,intravenous, etc.).

In some embodiments, ketamine and/or related compounds may beadministered once per day, hourly, twice per day, thrice per day, 4times per day, 5 times per day, 7 times per day or 10 times per day. Ina preferred embodiment, ketamine is administered once per day. Often thedosage is divided equally throughout the day, however in someembodiments to treat certain disorders or symptoms, it may be useful tobias the dosage administration schedule so that most of the dailytreatment is administered at the beginning half of the day. In someembodiments, about 50%, 60%, 70% or 80% of the dosage is administered inthe first half of the day. In other embodiments, it may be moreappropriate to administer most of the dosage in the latter half of theday so that about 50%, 60%, 70% or 80% of the dosage is administered inthe latter half of the day.

In some embodiments, the ketamine is administered at a dose from about0.15 mg/kg/hour to about 10 mg/kg/hour for at least two hours (e.g., 2,3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 72, 100, etc). In someembodiments, the ketamine is administered at a dose from about 0.15mg/kg/hour to about 5 mg/kg/hour for at least two hours (e.g., 2, 3, 5,10, 15, 20, 25, 30, 40, 50, 60, 70, 72, 100, etc). In some embodiments,the ketamine is administered at a dose from about 0.15 mg/kg/hour toabout 2 mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20,25, 30, 40, 50, 60, 70, 72, 100, etc). In some embodiments, the ketamineis administered at a dose from about 0.15 mg/kg/hour to about .5mg/kg/hour for at least two hours (e.g., 2, 3, 5, 10, 15, 20, 25, 30,40, 50, 60, 70, 72, 100, etc). In some embodiments, the ketamine isadministered at a dose from about 0.15 mg/kg/hour to about .3 mg/kg/hourfor at least two hours (e.g., 2, 3, 5, 10, 15, 20, 25, 30, 40, 50, 60,70, 72, 100, etc).

Administration of the compounds of this invention may be by any methodused for administering therapeutics, such as for example, oral,parenteral, intravenous, intramuscular, subcutaneous, intranasal,rectal, or topical administration, such as through the use of atransdermal patch.

It will be appreciated by one of ordinary skill in the art that age ofthe patient with the conditions described herein may respond totreatment at different degrees depending on factors such as dosage oradministration or the presence of other factors or co-morbid conditions.Therefore, one of ordinary skill in the art will appreciate that themethods described herein may be directed to a particular age group.

In addition to comprising the therapeutic compounds for use in thisinvention, especially ketamine or pharmaceutically acceptable salts orpro-drug thereof, the pharmaceutical compositions for use with thisinvention may also comprise a pharmaceutically acceptable carrier. Suchcarriers may comprise additives, such as preservatives, excipients,fillers, wetting agents, binders, disintegrants, buffers may also bepresent in the compositions of the invention.

Suitable additives may be, for example magnesium and calcium carbonates,carboxymethylcellulose, starches, sugars, gums, magnesium or calciumstearate, coloring or flavoring agents, and the like. There exists awide variety of pharmaceutically acceptable additives for pharmaceuticaldosage forms, and selection of appropriate additives is a routine matterfor those skilled in art of pharmaceutical formulation.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose. Unit doseforms for oral administration may be tablets, capsules, and the like,and may contain conventional excipients such as binding agents, forexample syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; and carriers or fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine. Additivesmay include disintegrants, for example starch, polyvinylpyrrolidone,sodium starch glycolate or microcrystalline cellulose; preservatives,and pharmaceutically acceptable wetting agents such as sodium laurylsulphate.

In addition to unit dose forms, multi-dosage forms are also contemplatedto be within the scope of the invention. Modified or controlled releasedosage forms are contemplated for use in the invention, including, butnot limited to sustained release dosage forms, extended release dosageforms, delayed release dosage forms, and pulsatile release dosage forms.

Suitable polymers for use in the controlled release formulations of thepresent invention include, but are not limited to uncrosslinked, linearpolymers including cellulosic polymers, preferably hydroxyethylcellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl celluloseand hydroxypropyl cellulose, microcrystalline cellulose, methylcellulose, and ethyl cellulose, and combinations thereof; covalentlycrosslinked insoluble polymers such as high molecular weight crosslinkedhomopolymers and copolymers of (meth) acrylic acid including carbopolresins, or mixtures of these uncrosslinked and covalently crosslinkedpolymers. Additionally suitable polymers include acrylic acid,methacrylic acid, methyl acrylate, ammonio methylacrylate, ethylacrylate, methyl methacrylate and/or ethyl methacrylate, vinyl polymersand copolymers such as polyvinyl pyrrolidone, polyvinyl acetate,polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, andethylene-vinyl acetate copolymers, to name a few. Various combinationsof two or more of the above polymers are also contemplated for use inthe dosage forms of the invention.

Delayed release compositions may be prepared, for example, by employingslow release coatings, micro encapsulation, and/or slowly dissolvingpolymers.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art. The tablets may be coated according to methods well known innormal pharmaceutical practice, for example with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminumstearate gel, and hydrogenated edible fats; emulsifying agents, forexample lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles(which may include edible oils), for example almond oil or fractionatedcoconut oil, oily esters such as esters of glycerine, propylene glycol,or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavoringor coloring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions, the compound can be dissolved in water or salinefor injection and filter sterilized before filling into a suitable vialor ampoule and sealing. Advantageously, additives such as a localanesthetic, preservative and buffering agent can be dissolved in thevehicle. Suitable buffering agents are, for example, phosphate andcitrate salts. To enhance the stability, the composition can be frozenafter filling into the vial and the water removed under vacuum.Parenteral suspensions are prepared in substantially the same manner,except that the compound is suspended in the vehicle instead of beingdissolved, and sterilization cannot be accomplished by filtration. Thecompound can be sterilized by conventional means, for example byexposure to radiation or ethylene oxide, before being suspended in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The ketamine and, optionally, at least one additional compound may beprovided in a kit. In one embodiment, a kit may comprise at leastketamine and at least one additional compound. In one embodiment, a kitmay comprise at least ketamine, L-DOPA or other dopamine-related drug,and optionally at least one additional compound. In a furtherembodiment, a kit as in any one of the previously described may alsoinclude instructions for administration of the compounds. In oneembodiment, the kit is intended for use by a subject having PD.

EXPERIMENTAL Example I

The following examples are illustrative, but not limiting, of thecompounds, compositions, and methods of the present invention. Othersuitable modifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art are within the spirit and scope ofthe invention.

Materials and Methods

Study Approval: The human case report study was approved by theInstitutional Review Board, University of Arizona and written informedconsent was received from participants. All animals were treated asapproved by the Institutional Animal Care and Use Committee, Universityof Arizona and in accordance with the NIH Guidelines for the Care andUse of

Laboratory Animals. Both the number of animals used and their sufferingwere minimized.

Animals: Male Sprague-Dawley rats (250 g; Harlan Laboratories,Indianapolis, IN) were used and housed in a temperature and humiditycontrolled room with 12 hr reversed light/dark cycles with food andwater available ad libitum. Unilateral 6-hydroxydopamine (6-0HDA)-lesionrat PD model: 20 _(l)ag 6-OHDA hydrochloride (Sigma—Aldrich, USA) wereinjected into the medial forebrain bundle, as published (Flores et al.,2014).

Induction of LID in unilaterally-lesioned rats: 1) Amphetamine-inducedipsiversive rotations were recorded, as published (Yue et al., 2011), toselect animals. Mean ipsiversive rotations/min±SEM: cohort #1=5.5±0.7(n=5); cohort #2=6.9±1.1 (n =10). 2) Rats were treated daily for 3 weekswith L-DOPA+14 mg/kg benserazide; both i.p.; Sigma-Aldrich): cohort #1(severe dyskinesia): 7 mg/kg L-DOPA; cohort #2 (moderate dyskinesia): 5mg/kg L-DOPA.

Behavioral analysis in the LID rat model: L-DOPA-induced AIMs werescored by an experimentally blinded investigator, as published (Floreset al., 2014). At the end of the experiment the rats were euthanized,and 30 minutes prior both cohorts were divided into 2 groups receivingeither a 20 mg/kg ketamine or saline injection (i.p.).

Measurement of dopamine content: Coronal brain slices were collected and2 mm steel biopsy punches were used to sample striatal tissue. Samplesfrom left and right hemispheres were collected and immediately flashfrozen on an aluminum pan at −70° C., as published (Flores et al.,2014). Samples massed at 2.5±0.5 mg and were then homogenized in diluteperchloric acid. High performance liquid chromatography withelectrochemical detection (HPLC-EC) was used to quantify DA.

Western analysis of tyrosine hydroxylase (TH) content: After the tissuepunch, described above, the remaining striata from left and righthemispheres were immediately flash frozen and stored at —70 ° C. Totalprotein was prepared and semi-quantitative western analysis wasconducted as described (Flores et al., 2014; Yue et al., 2014) with 3modifications. 30 μg of protein/sample was loaded and analyzed on thesame blot. Secondary antibody dilution for β-actin: 1:10,000. Imageswere analyzed with the G:Box XR5 Chemi system (Syngene, Frederick, Md.)using GeneSys v. 1.4.0.0.

Data Analysis: Statistical analysis was performed using GraphPad Prism5.1 software (GraphPad Software, La Jolla, Calif.), Origin 9.0(OriginLab Corporation, Northampton, Mass.) and Microsoft Excel 2013.The null hypothesis was rejected when p<0.05.

Results

We report on five cases of low-dose ketamine infusion in patients withPD identified by a retrospective chart review (Table 1). Ketamine wasindicated for a variety of co-morbid conditions. The level ofdocumentation of PD and LID symptoms pre and post-infusion was variable,but in many cases included standardized clinical rating scales collectedby Movement Disorder specialists. Overall, the case reports indicateexcellent tolerability and safety of ketamine in this group of patients.Patients were treated in the intensive care unit using a protocoldeveloped by one of the authors (ME) for treatment of intractableheadache that specified titration of ketamine to a target rate of 0.15mg/kg/hr for a 72 hr period. Variations in the dosing are shown in Table1.

TABLE 1 Patient details. Clinical effects of ketamine DemographicsKetamine fusion side case Disease Hohn L-DOPA starting max durationaverage UPDRS pt 3 pain effects # age sex Duration Yahr Equiv.indication dose dose (hours) dose before during after before duringafter RASS 1 64 m 20 3 2400 back pain 0.05 0.3 50 nd nd nd nd nd nd ndnd 1-8 67 m 23 4 3208 back pain 0.1 0.3 67 0.24 48 18 40 8 1 1 0.20 2 62m >10 3 2150 painful 0.15 0.15 72 0.15 nd nd nd nd nd nd nd dyskinesia 384 m 12 3 1971 back pain 0.05 0.15 66 0.08 40.5 nd 28 5 0.73 0 0.14 4 46f 6 2.5 400 headache 0.05 0.16 96 0.09 nd nd nd 10 5.5 5 0.42 5 54 f 82.5 400 headache 0.05 0.16 72 0.12 nd nd nd nd nd nd nd nd, notdetermined; UPDRS, unified Parkinson’s disease rating scale; 0-10 PainScale Assesment; RASS, Richmond Agitation Sedation Scale

Case #1 demonstrates a remarkable observation of resolution of LID in apatient with long-standing PD who routinely completed all-day diaries ofhis motor fluctuations, and underwent close clinical observation (FIG.1A, B). This patient was treated for intractable back pain due to severelumbar degenerative disk disease which was exacerbated by often severeand violent dyskinesia. During admission, no adjustments were made tothe dosages of carbidopa/L-DOPA or other medications, yet his dyskinesiaimproved markedly during and after the infusion. He was free ofdyskinesia at the time of a second infusion 3 years later despite anincrease in L-DOPA dose. At that time the patient was noted to havesevere tremor, which resolved acutely during the infusion. Unlike thedyskinesia, the beneficial effect on tremor was short-lived since thetremor had returned at a follow-up visit 3 weeks later. The patientcontinues to be followed by one of the investigators (SJS) and hasremained free of dyskinesia.

Similarly, in case #2 there was a dramatic reduction in dyskinesia asreported by one of the authors (ME) though less quantitative data isavailable from chart review. Notably, prior amantadine (200 mg daily)treatment had failed to improve his LID.

Case #3 was a patient with severe back pain, depression, and advancedPD. Ketamine dramatically improved the patient's depression, pain, andacutely improved his motor symptoms. The patient had significantcomorbid medical problems including reduced cardiac ejection fraction,and arrhythmia. Though dyskinesia was not the most prominent feature ofhis motor symptomatology, it is notable that it completely subsidedfollowing the infusion, and that there was acute improvement in otheraspects of the motor exam during the infusion. His depression wasdramatically improved (Table 1, patient was suicidal before infusion andonly mildly depressed on subsequent follow-up visits, followed by SJS).This case supports the safety and feasibility of using low-dose ketamineeven in patients of advanced age and with comorbid conditions.

Cases #4 and 5 had intractable headache and relatively early-onset PD,treated with subthalamic nucleus (STN) deep brain stimulation (DBS)which had previously resolved their dyskinesia and motor fluctuations.In case #4 the headache occurred after DBS placement and may have beenrelated to hardware placement, in case #5 the headache preceded DBSplacement. The headache was improved in case #4, but in case #5 thepatient requested the infusion be aborted due to non-efficacy andnon-specific side effects. These cases are included for completeness ofdocumentation and safety data but there was little effect on motorsymptoms. Though in case #4, the intensity of DBS stimulation wasreduced by 0.3 volts bilaterally with improvement of stimulation induceddysarthria without loss of motor benefit.

Preclinical data: Studies were conducted in the standard preclinical ratLID model (Dekundy et al., 2007). Verification for the unilateral lesionin both cohorts is shown in FIG. 2A, B. The rats in cohort #1 showedsevere LID and a dose-dependent long-term anti-dyskinetic effect oflow-dose ketamine when given for a 10 hr period was demonstrated (FIG.3A,B); to mimic the patient infusion ketamine was injected 5 x i.p. twohrs apart, 7 mg/kg L-DOPA was co-injected at the 5^(th) injection, andthen the abnormal involuntary movements-(AIMs) scores were evaluated.This approach was used as it is not possible to use a regular infusionin a behaving rat and given the long-term nature of the experimentclogging of surgically inserted mini-pumps was a concern. After a 5mg/kg ketamine-‘infusion’, there was a reduction of the AIMs score thatlasted 7 days post-injection, before the baseline level (black dashedline) was reached again. After the 10 mg/kg ketamine-‘infusion’ it took10 days before the baseline AIMs score was reached again and after the15 mg/kg ketamine-‘infusion’, it took 31 days before the baseline AIMsscore level was reached again. Most impressive, however, was the effectof 20 mg/kg ketamine-‘infusion’, which resulted in a persistentreduction of AIMs scores that lasted for at least 55 dayspost-injection, and what appeared to be a new lower stable AIMs levelwas established (blue dashed line). A 10 mg/kg ketamine-‘infusion’ wasgiven after these treatments to test for sensitization resulting fromketamine treatment. No change in the already-reduced AIMs score wasobserved following this dosage, suggesting that reduced AIMs scoresfollowing the 20 mg/kg injection was not due to sensitization. At allthe tested doses ketamine did not significantly change L-DOPA-inducedcontralateral locomotor behavior (FIG. 3C), and specifically did notacutely induce the ipsiversive turning behavior that is indicative of aworsening of the Parkinsonism in this model, as it has been shown by thenon-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801(Flores et al., 2014; Paquette et al., 2010). To investigate if thelonger exposure to ketamine is necessary a separate cohort #2 of ratswith moderate LID was tested to see if an acute ketamine injection wouldalso be anti-dyskinetic (FIG. 3D). The rats were primed and tested with5 mg/kg L-DOPA, and two acute i.p. injections of 15 mg/kg ketamine(fourteen days apart) did not lead to any change in the AIMs scores.

Example II

This example demonstrates that a low-dose sub-anesthetic racemicketamine infusion once a week reduces the development of LID in apreclinical model. Unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PDrats were injected daily with L-DOPA (days 0-13: 6 mg/kg; days 14-28: 12mg/kg; i.p.) to induce dyskinesia and tested for limb, axial and oral(LAO) abnormal involuntary movements (AIMs) twice a week for 3 hours byblinded investigators.

FIG. 4A shows the mean LAO AIMs scores±SEM are plotted showing a 50%reduction after racemic low-dose ketamine infusions. The black arrowspoint to the days of the 10-hours racemic ketamine, R-ketamine orvehicle infusion paradigm (n=9 per group, *p<0.05, ANOVAs, Tukey posthoc tests).

FIG. 4B and 4C present scatter plots depicting every animal separatelyin both the 6 mg/kg L-DOPA period in (B) and the 12 mg/kg L-DOPA periodin (C) reveal that there are responders and non-responders in theracemic ketamine-treated group: 4 of 9 animals did not develop anydyskinesia or only very subtle dyskinesia, while only 1 in theR-ketamine-treated group, and none in the vehicle control group. Theblack lines depict the mean value per groups.

This data indicates that racemic ketamine infusions reduces thedevelopment of dyskinesia and therefore is indicative for early use inthe treatment of L-DOPA-induced dyskinesia.

Example III

This example describes the effects of racemic ketamine injection (20mg/kg) on high-frequency (HFO) and beta band oscillations in the motorcortex (M1) and dorsolateral striatum (DLS).

Using the 10-hour racemic ketamine paradigm (5 i.p. injections every 2hours), simultaneous local-field activity in multiple brain structuresin two awake and behaving naive rats was measured. Recordings wereacquired from a 64 channel fixed electrode array. Average responseacross 2 animals and 5 sessions was obtained.

FIG. 5A and B shows power spectrogram from a 10 hour session created byaveraging spectra acquired from 5 recording sessions. Vertical linesindicate K injection times. A clear increase in high-frequency activity(120-140 Hz) was observed after each ketamine injection in both motorcortex (M1) and dorsolateral striatum (DLS).

FIG. 5C shows a plot of mean coherence in all frequencies <200 Hz.Coherence in the HFO frequency band increased following each injection.

FIG. 5D shows a plot of the mean coherence in the HFO and beta bands(n=5 sessions). Thin lines indicate SEM. Coherence in these two bandswas anti-correlated (r=−0.65). Coherence in the HFO band appeared toincrease with successive injections while coherence in the beta banddecreased.

Accordingly, as decoupling of beta and gamma band activity in motorcortex is indicated as one of the mechanisms of action for deep brainstimulation (DBS) in the subthalamic nucleus to treat PD patients, theseresults demonstrate that low-dose ketamine infusions act as a ‘chemicalDBS’.

Example IV

This example describes the effects of racemic ketamine injection (20mg/kg) on high-frequency (HFO), gamma and beta band oscillations in themotor cortex (M1) and dorsolateral striatum (DLS) of a rodentParkinson's disease model.

Using a 10-hour racemic ketamine paradigm (5 i.p. injections every 2hours), simultaneous measurement of local-field activity in multiplebrain structures in three awake and behaving unilateral6-hydroxydopamine (6-OHDA)-lesioned rats, a common model of Parkinson'sdisease. Recordings were acquired from a 64 channel fixed electrodearray. Average response across 3 animals. Power spectrogram from a 10hour session created by averaging spectra acquired. Vertical linesindicate ketamine injection times.

FIG. 6A and B show a clear increase in high-frequency activity (120-140Hz) and gamma band activity (40-60 Hz) was observed after each ketamineinjection in both DLS (A) and M1 (B).

FIG. 6C shows beta-gamma cross-frequency coupling (CFC) in the DLS of6-OHDA-lesioned PD animals is reduced following each ketamine injection.Units are in z-scores relative to baseline CFC during the 20 minutesprior to the first injection. Cross-frequency coupling measures thedegree to which fluctuations in the power of the high-frequencyoscillation (gamma) is correlated with the phase of the lower-frequencyoscillation (beta). Error bars indicate SEM (n=15 sessions across 3animals).

This data is in further support of the hypothesis that low-dose ketamineinfusions act as a ‘chemical DBS’.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

REFERENCES

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We claim:
 1. (canceled)
 2. A method of attenuating and/or treating ahuman patient suffering from dyskinesia, comprising administering to thehuman patient within a ten-day period two or more doses of a compositioncomprising a dose of ketamine or a pharmaceutically acceptable saltthereof, wherein each dose is at least a two hour administration of 0.15mg/kg/hour to about 2 mg/kg/hour of ketamine or a pharmaceuticallyacceptable salt thereof.
 3. The method of claim 2, wherein thedyskinesia is levodopa induced dyskinesia.
 4. The method of claim 2,wherein each of the doses are administered via infusion delivery,intranasal delivery, transdermal delivery, oral delivery, or intravenousdelivery.
 5. The method of claim 2, wherein administering thecomposition results in the patient experiencing chemical-induced deepbrain stimulation.
 6. The method of claim 5, wherein thechemical-induced deep brain stimulation results in attenuation and/ortreating of the symptoms of the dyskinesia. (New) The method of claim 2,further comprising administration of carbidopa.
 8. The method of claim2, wherein the human subject is suffering from Parkinson's disease. 9.The method of claim 2, wherein the at least two hour administration isat least three hours.
 10. The method of claim 2, wherein the at leasttwo hour administration is at least four hours.
 11. The method of claim2, wherein the at least two hour administration is at least five hours.12. The method of claim 2, wherein the at least two hour administrationis at least six hours.
 13. The method of claim 2, wherein the at leasttwo hour administration is at least seven hours.
 14. The method of claim2, wherein the at least two hour administration is at least eight hours.15. The method of claim 2, wherein the at least two hour administrationis at least nine hours.
 16. The method of claim 2, wherein the at leasttwo hour administration is at least ten hours.
 17. The method of claim2, wherein the within a ten-day period is within 72 hours
 18. The methodof claim 2, wherein ketamine is a metabolite of ketamine, wherein themetabolite of ketamine is selected from R-norketamine (NK),R-dehydronorketamine (DHK), S-norketamine (NK), S-dehydronorketamine(DHK), (2R,6R)-hydroxynorketamine (HNK), and (2S,6S)-hydroxynorketamine(HNK).
 19. A device for attenuating and/or treating a human patientsuffering from dyskinesia, wherein the device is configured to deliverto the human patient over at least a two hour period a dose of about0.15 mg/kg/hour to about 2 mg/kg/hour of ketamine or a pharmaceuticallyacceptable salt thereof.
 20. The device of claim 2, wherein the deviceis configured for transdermal delivery of the dose, infusion delivery ofthe dose, intranasal delivery of the dose, oral delivery of the dose, orintravenous delivery of the dose.